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WO2013036676A1 - Inhibiteurs du vih - Google Patents

Inhibiteurs du vih Download PDF

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Publication number
WO2013036676A1
WO2013036676A1 PCT/US2012/054009 US2012054009W WO2013036676A1 WO 2013036676 A1 WO2013036676 A1 WO 2013036676A1 US 2012054009 W US2012054009 W US 2012054009W WO 2013036676 A1 WO2013036676 A1 WO 2013036676A1
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WO
WIPO (PCT)
Prior art keywords
isomers
independently
optionally substituted
alkyl
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2012/054009
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English (en)
Inventor
Asim Kumar Debnath
Francesca Curreli
Peter D. Kwong
Young Do KWONG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New York Blood Center Inc
US Department of Health and Human Services
Original Assignee
New York Blood Center Inc
US Department of Health and Human Services
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New York Blood Center Inc, US Department of Health and Human Services filed Critical New York Blood Center Inc
Priority to CA2845933A priority Critical patent/CA2845933C/fr
Priority to EP12830850.9A priority patent/EP2753176A4/fr
Priority to US14/241,329 priority patent/US9309237B2/en
Publication of WO2013036676A1 publication Critical patent/WO2013036676A1/fr
Priority to IL231269A priority patent/IL231269B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/40—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to the field of HIV-inhibitors.
  • HIV-1 Human immunodeficiency virus type 1
  • AIDS acquired immunodeficiency syndrome
  • UAIDS AIDS Epidemic Update
  • HAART highly active anti-retroviral therapy
  • HIV-1 infection involves the attachment of the virus to the host cell, reverse transcription of genetic material from viral RNA to DNA, integration of viral DNA with host DNA, replication of viral RNA from DNA, translation of viral RNA to create viral proteins, cleavage of viral proteins, assembly and packaging of viral proteins, and budding from the host cell.
  • HIV-1 infection of a host immune cell first requires attachment of the virus to the cell membrane.
  • a receptor On the surface membrane of all living cells are complex protein structures called "receptors". A receptor is often compared to a lock into which a specific key or "ligand” will fit. Attachment of the virions to receptors on the host membrane enables fusion and the viral contents, including viral RNA, will empty into the cell's cytoplasm. Like other viruses that infect human cells, HIV-1 commandeers the host's machinery to make multiple copies of itself. Once the RNA has been copied and translated into proteins, the viral RNA and associated proteins are packaged and released from the host cell, taking with them a piece of the cell membrane. [0006] There are only nine genes in the HIV-1 genome. These genes have the code necessary to produce structural proteins, such as the viral core and enzymes like reverse transcriptase, integrase, and protease.
  • FIG. 1 depicts GLIDE (Grid-base ligand docking with energetics) of compound 6 in the Phe43 cavity of CD4 bound to pp120 of HIV-1.
  • FIG. 1A Compound 6 is shown docked inside the cavity. The 4-chlorophenyl moiety is located deep inside the cavity. The protonated “N” of the piperidine ring is within the salt-bridge (H-bond interaction) distance from Asp368.
  • FIG. 1 B The interactions of compound 6 with the residues in the "Phe43 cavity" of HIV-1 gp120 as mapped by the Maestro software in Schrodinger Suit 201 1 .
  • FIG. 2 depicts the structures of NBD-556 and NBD-557 identifying different pharmacophoric regions.
  • R CI
  • R Br
  • FIG. 3 depcits binding of compounds 27 and 39.
  • the docking-based top scored conformations of 27 demonstrated distinct differences in binding of the piperidine-thiazolyl moiety.
  • the piperidine NH formed an H-bond/salt-bridge with Asp368 in the seoncd best scored conformation but not in the top scored conformation (FIG. 3A and 3B).
  • Both top scored conformations of 39 formed the H-bond/salt-bridge with Asp368 (FIG. 3C and 3D).
  • FIG. 4 depicts cell-cell fusion (FIG. 4A) and virus-cell fusion (FIG. 4B) experiments.
  • FIG. 5 depicts the inhibitor activity of compound on the infections of a CD4 dependent virus (ADA) in Cf2Th-CD4+-CCR5+ target cells that express CD4 and CCR5.
  • ADA CD4 dependent virus
  • FIG. 6 depicts dose-response plots of the neutralization assay using MT-2 cells with HIV-1 V32 (FIG. 6A) and PBMC (FIG. 6B) with the HIV-1 92BR025 isolate (subtype C and R5-tropic).
  • FIG. 7 depicts inhibition of the gp120-CD4 interaction by NBD-09027, NBD- 10007 and NBD-556 in a dose dependent manner.
  • FIG. 8 depicts a single-cycle antiviral assay inhibition of HIV infection in TZM-b1 cells by NBD-09027 and NBD-10007 (FIG. 8A) and NBD-1 1008, NBD-1 1009, NBD-1 1017, and NBD-1 1018 (FIG. 8B).
  • FIG. 9 depicts inhibition of virus-cell fusion between U87-CD4-CCR5 cells and R5 tropic virus (FIG. 9A) or between U87-CD4-CXCR4 and X4 tropic virus (FIG. 9B) by the disclosed compounds.
  • HIV human immunodeficiency virus
  • Some embodiments include a pharmaceutical composition, such as an antiviral composition, comprising a compound represented by a formula:
  • Ph 1 is optionally substituted phenyl or optionally substituted C 4 - 8 cycloalkyl; R' is a bond or Ci_ 3 alkyl; Ar 1 is optionally substituted phenyl or optionally substituted C 2- 5 heteroaryl; and Cy 1 is optionally substituted aliphatic C 3 - 6 heterocyclyl, or (CH 2 ) b NR u R v , wherein R u and R v are independently H or Ci -3 alkyl; and b is 0 or 1.
  • Some embodiments include a pharmaceutical composition, such as an antiviral composition, comprising a compound represented by a formula:
  • Ph 2 is optionally substituted phenyl
  • L 1 is -R w - -R w NHCO- -R w OCO, or -R w CO- wherein R w is a bond or C 1-6 alkyl optionally substituted with 1 or 2 substituents, wherein each substituent is independently OH, F, CI, Br, or I
  • Cy 2 is an optionally substituted C3-15 carbocyclic ring or ring system, an optionally substituted C 3- i 5 heterocyclic ring or ring system, or NR x R y , wherein R x and R y are independently H or Ci -3 alkyl.
  • Some embodiments include a pharmaceutical composition, such as an antiviral compositions, comprising a compound represented by a formula:
  • G 1 is an optionally substituted C 6- io bicyclic ring system, wherein at least one ring of the ring system contains a nitrogen atom or an oxygen atom; s is 0 or 1 ; R 6 and R 7 are independently a bond or C 1-3 alkyl; Ar 2 is optionally substituted monocyclic C 2- 5 heteroaryl; and Cy 3 is optionally substituted aliphatic C 2-5 heterocyclyl.
  • composition further comprising at least one pharmaceutically acceptable excipient.
  • composition further comprising at least one additional therapeutically active agent.
  • a method for inhibiting infection with HIV or treating HIV infection comprising: administering to a patient in need thereof a composition comprising a pharmaceutically effective amount of a compound according to formulas l-V, or a pharmaceutically acceptable salt or ester thereof.
  • the method further comprises administering at least one additional therapeutic agent selected from the group consisting of reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, chemokine receptor (CXCR4, CCR5) inhibitors, interleukin-2, hydroxyurea, monoclonal antibodies, and cytokines.
  • HIV capsid or "capsid” include an ordered icosahedral particle composed of approximately 1500 Gag polypeptides within which is normally housed HIV-1 specific genomic material and enzymes.
  • the capsid is first formed as an immature structure, and later undergoes a "maturation” event mediated by a HIV-specific protease.
  • the HIV- specific protease cleaves Gag polypeptides that form the immature capsid into smaller proteins. This results in a change in the shape of the capsid to the mature, cone shaped capsid.
  • the terms “inhibit,” “inhibition,” “inhibitory” and “inhibitory activity” include slowing, decreasing, interrupting, arresting or suppressing HIV assembly, maturation and replication activity so as to enable prolonging the survivability of the patient.
  • the claimed composition may suppress 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the retroviral activity.
  • IC 50 is well understood by a person of skill in the art to be the accepted measure of the effectiveness of inhibition. The measurement indicates how much of a particular substance is necessary to decrease or inhibit a particular activity by 50%.
  • a "small molecule” includes an organic molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 3 kD, 2 kD, or 1 kD. In some embodiments, a small molecule is less than about 800 daltons (D), 600 D, 500 D, 400 D, 300 D, 200 D, or 100 D. In some embodiments, small molecules are non-polymeric. In some embodiments, small molecules are not proteins, peptides, or amino acids. In some embodiments, small molecules are not nucleic acids or nucleotides. In some embodiments, small molecules are not polysaccharides.
  • kD kilodaltons
  • terapéuticaally effective amount or “pharmaceutically effective amount” include an amount of composition sufficient to, when administered to a subject suffering from or susceptible to HIV infection and/or one or more associated diseases, disorders or conditions, cause a detectable effect in treating HIV infection and/or associated disease(s), disorder(s) or condition(s).
  • treat refers to partially or completely alleviating, inhibiting, preventing, curing, delaying the onset of, reducing incidence of, ameliorating and/or relieving one or more symptoms or features of a particular disease, disorder or condition (e.g., HIV infection).
  • a particular disease, disorder or condition e.g., HIV infection
  • a human immunodeficiency virus may enter cells when its envelope glycoprotein gp120 binds to the primary cellular receptor CD4.
  • Two HIV glycoproteins gp120 and gp41 may be assembled as a trimer.
  • An HIV infection in human T-cell lymphocytes may occur via binding of gp120 to the host T-cell CD4 receptor followed by gp120 conformational change. This conformational change may expose on gp120 the binding site for the chemokine receptor, either CCR5 or CXCR4, thus exposing gp41 and permitting the second obligatory binding event for viral entry.
  • Chemokine receptor binding may be followed by insertion of the gp41 fusion peptide in the host cell membrane, allowing fusion and viral entry.
  • Binding of gp120 and CD4 may create a roughly spherical 152 A° cavity at this location. This cavity may extend deep into the interior of gp120 and may be bounded by amino acid residues from each of the gp120 core domains. These cavity-lining gp120 residues may be highly conserved among HIV-1 strains.
  • Phe43 of CD4 which may alone accounts for 23% of the total contacts with gp120, may be the major hydrophobic reside in CD4 that binds this cavity. Hence, the cavity may be designated the Phe43 cavity.
  • CD4 may be bound into a depression formed at the interface of the outer domain with the inner domain and the bridging sheet of gp120. This interaction may burys a total of 742 A 2 from CD4 and 802 A 2 from gp120.
  • Insertions into this cavity may enhance the affinity of CD4 and CD4 mimetics and thus there is a need for small molecule compounds which insert into the Phe43 cavity and thus inhibit HIV infection.
  • NBD-556 and NBD557 Two compounds which may demonstrate conformations changes in gp120 similar to CD4 at low micromolar potency are NBD-556 and NBD557.
  • the distal NH of the oxalamide group from 4-chlorophenyl ring forms an H-bond with Gly473.
  • the tetramethylpiperidine moiety can be replaced with other groups that may be able to take advantage of additional interactions, such as with Asp368, near the entrance of the cavity and yield more potent antivirals.
  • a compound or chemical structural feature such as aryl when referred to as being “optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is "substituted,” meaning that the feature has one or more substituents.
  • substituted has the broadest meaning known to one of ordinary skill in the art, and includes a moiety that replaces one or more hydrogen atoms attached to a parent compound or structural feature.
  • a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g.
  • a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, CI, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, CI, Br, or I atom.
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalome
  • molecular weight is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.
  • alkyl has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen containing no double or triple bonds.
  • Alkyl may be linear alkyl, branched alkyl, cycloalkyi, or a combination thereof, and in some embodiments, may contain from one to thirty-five carbon atoms.
  • alkyl may include CMO linear alkyl, such as methyl (-CH 3 ), ethyl (-CH2CH3), n-propyl (-CH 2 CH 2 CH 3 ), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), etc.; C3-10 branched alkyl, such as C3H7 (e.g. iso-propyl), C 4 H 9 (e.g. branched butyl isomers), CsHu (e.g.
  • CMO linear alkyl such as methyl (-CH 3 ), ethyl (-CH2CH3), n-propyl (-CH 2 CH 2 CH 3 ), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), n-
  • branched pentyl isomers C 6 H 13 (e.g. branched hexyl isomers), C 7 H 15 (e.g. heptyl isomers), etc.; C3-10 cycloalkyi, such as C 3 H 5 (e.g. cyclopropyl), C 4 H 7 (e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C 5 H 9 (e.g. cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.) C 6 Hn (e.g. cyclohexyl isomers), C 7 H 13 (e.g. cycloheptyl isomers), etc.; and the like.
  • C 3 H 5 e.g. cyclopropyl
  • C 4 H 7 e.g. cyclobutyl isomers such as cyclobut
  • optionally substituted Ci_i 2 alkyl refers to a Ci_i 2 alkyl that may be unsubstituted, or may have 1 or more substituents, and does not limit the number of carbon atoms in any substituent.
  • a phrase such as optionally substituted alkyl refers to unsubstituted alkyl, or substituted alkyl wherein both the alkyl parent and all substituents have from 1 -12 carbon atoms. Similar conventions may be applied to other optionally substituted moieties such as aryl and heteroaryl.
  • Substituents on an alkyl may be the same as those described generally above, except that alkyl may not have an alkyl substituent.
  • substituents on an alkyl may be independently selected from F, CI, Br, I, OH, CN, C0 2 H, -O-alkyl, ester groups, acyl, amine groups, and amide groups, and may have a molecular weight of about 15 to about 100 or about 15 to about 500.
  • aryl has the broadest meaning generally understood in the art, and may include an aromatic ring or aromatic ring system such as phenyl, naphthyl, etc.
  • heteroaryl also has the meaning understood by a person of ordinary skill in the art, and includes an "aryl” which has one or more heteroatoms in the ring or ring system, such as pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc.
  • any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • pharmaceutically acceptable salts such as sodium, potassium, and ammonium salts
  • prodrugs such as ester prodrugs
  • tautomers or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • a dashed line represents the presence or absence of a double bond.
  • Ph 1 may be optionally substituted phenyl or optionally substituted C 4 - 8 cycloalkyl, such as optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl, etc. If the phenyl is substituted, it may have 1 , 2, 3, 4, or 5 substituents. If the cycloalkyl is substituted, each atom of the ring may independently have 0, 1 , or 2 substitutents. In some embodiments, the cycloalkyl, may have 0, 1 , 2, 3, 4, 5, 6, 7, or 8 substituents.
  • any substituent may be included on the phenyl or cycloalkyl.
  • some or all of the substituents on the phenyl or cycloalkyl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least 1 non- hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H , cyclic C 5 H 9 , C 6 H 13 , cyclic CeHu , etc., which may be optionally substituted; C 1 -10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCH 3 , -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 -phenyl
  • Ph 1 may be phenyl optionally substituted with 1 or 2 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ph 1 is cycloheptyl optionally substituted with 1 or 2 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ph 1 may be:
  • Ph 1 may be:
  • R' may be a bond or C 1-3 alkyl, such as CH 2 , C 2 H 4 (e.g. -CH 2 CH 2 - or -CH(CH 3 )-), C 3 H 6 (e.g. -(CH 2 ) 3 -, -CH 2 CH(CH 3 )-, etc.), cyclic C 3 H 4 , etc.
  • R' is a bond.
  • R' is CR 8 R 9 .
  • R' is CH 2 .
  • R' is C 2 H 4 .
  • Ar 1 may be optionally substituted phenyl or optionally substituted C 2-5 heteroaryl, such as thiazolyl, pyridinyl, furyl, thienyl, etc. If the phenyl is substituted, it may have 1 , 2, 3, 4, or 5 substituents. If the heteroaryl is substituted, each carbon atom of the ring may independently have 0 or 1 substitutent. In some embodiments, the heteroaryl may have 0, 1 , 2, 3, or 4 substituents. Any substituent may be included on the phenyl or heteroaryl.
  • some or all of the substituents on the phenyl or heteroaryl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be Ci-io optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , CeHu, cyclic C 5 H 9 , C 6 H 13 , cyclic CeHu, etc., which may be optionally substituted; CMO optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; Ci -6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCH 3 , -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 -phenyl, etc.;
  • Ar 1 is thiazolyl optionally substituted with 1 or 2 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ar 1 is pyridinyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ar 1 is phenyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ar 1 is furyl optionally substituted with 1 or 2 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ar 1 may be:
  • Ar 1 may be:
  • Ar 1 may be:
  • Ar 1 may be:
  • Cy 1 may be optionally substituted aliphatic C 3- 6 heterocyclyl, or (CH 2 ) b NR u R v . If the heterocyclyl is substituted, each carbon atom of the ring may independently have 0, 1 , or 2 substituents. In some embodiments, the heterocyclyl may have 0, 1 , 2, 3, or 4 substituents. Any substituent may be included on the heterocyclyl.
  • some or all of the substituents on the heterocyclyl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 Hn , etc., which may be optionally substituted; Ci-i 0 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; Ci -6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCHs, -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 -phenyl
  • Cy 1 is piperidinyl optionally substituted with 1 , 2, 3, or 4 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Cy 1 is pyrrolidinyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Cy 1 is azepanyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , 0R C , COR c , or R c -OH.
  • Cy 1 is piperizinyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Cy 1 is morpholino optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Cy 1 may be NR U R V or CH 2 NR U R V .
  • R u may be H, or Ci -3 alkyl such as CH 3 , C 2 H 5 , C 3 H 7 , cyclopropyl, etc. In some embodiments, R u is -CH 2 CH 3 . In some embodiments, R u is H.
  • R v may be H, or Ci -3 alkyl such as CH 3 , C 2 H 5 , C 3 H 7 , cyclopropyl, etc.
  • R v is -CH 2 CH 3.
  • R v is -CH 2 CH 3.
  • R v is CH 3.
  • R v is H and R u is CH 3 .
  • Cy 1 is -N(CH 2 CH 3 ) 2 . In some embodiments, Cy 1 is -CH 2 NHCH 3 .
  • Cy 1 may be:
  • Cy 1 may be:
  • Cy 1 may be:
  • Cy 1 may be:
  • Cy 1 may be:
  • Cy 1 may be:
  • Cy 1 may be:
  • Cy 1 may be:
  • L 1 may be -R w - -R w NHCO- -R w OCO-, or -R w CO-.
  • R w may be a bond or d -6 alkyi, such as C-i alkyi, C 2 alkyi, C 3 alkyi, C 4 alkyi, C 5 alkyi, C 6 alkyi, etc., wherein the alkyi is optionally substituted with 1 or 2 substituents, wherein each substituent is independently OH, F, CI, Br, or I.
  • R w is C 1-3 alkyi optionally substituted with one OH substituent.
  • L 1 is -CH 2 CHOHCH 2 -. In some embodiments, L 1 is -(CH 2 ) 3 NHCO-. In some embodiments, L 1 is CH 2 . In some embodiments, L 1 is -(CH 2 ) 3 - In some embodiments, L 1 is a bond.
  • Ph 2 may be optionally substituted phenyl. If the phenyl is substituted, it may have 1 , 2, 3, 4, or 5 substituents. Any substituent may be included on the phenyl. In some embodiments, some or all of the substituents on the phenyl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be C 1-10 optionally substituted alkyi, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H , cyclic C 5 H 9 , C 6 H 13 , cyclic CeHu, etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; Ci -6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCHs, -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 -phenyl, etc.
  • Ph 2 has 1 , 2, or 3 substituents, wherein each substituent is independently benzomidazol-2-yl, F, CI, Br, R c , OR c , COR c , or R c -OH, wherein each R c is independently C 1-6 alkyi.
  • Ph 2 may be:
  • Ph 2 may be:
  • Cy 2 may be an optionally substituted C3-15 carbocyclic ring or ring system, an optionally substituted C 3- i 5 heterocyclic ring or ring system, or NR x R y . If the ring or ring system is substituted, each carbon atom of a ring may independently have 0, 1 , or 2 substituents. In some embodiments, the ring or ring system may have 0, 1 , 2, 3, or 4 substituents. Any substituent may be included on the ring or ring system.
  • some or all of the substituents on the ring or ring system may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be CMO optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 Hn, cyclic C5H 9 , C 6 H 13 , cyclic C 6 Hn, etc., which may be optionally substituted; CMO optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; Ci -6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCH 3 , -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 - phenyl,
  • Cy 2 is piperidinyl optionally substituted with 1 , 2, 3, or 4 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , OH, COR c , or R c -OH.
  • Cy 2 is pyridinyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , OH, COR c , or R c -OH
  • Cy 2 is tetrahydroquinolinyl optionally substituted with 1 , 2, or 3 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , OH, COR c , or R c -OH.
  • Cy may be:
  • Cy 2 may be:
  • Cy 2 may be:
  • Cy 2 may be: [0081] In some embodiments, Cy may be:
  • Cy may be:
  • Cy may be:
  • Cy may be:
  • Cy may be: [0086] With respect to any relevant formula or structural depiction herein, such as Formula 5, R x may be H, or C 1-3 alkyl, such as CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CI-I 3 , etc. In some embodiments, R x is -CH 2 CH 3 .
  • R y may be H, or C 1-3 alkyl, such as CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 3 , etc. In some embodiments, R y is -CH 2 CH 3
  • Cy 2 is -N(CH 2 CH 3 ) 2 .
  • G 1 may be an optionally substituted C 6 -io bicyclic ring system, wherein at least one ring of the ring system contains a nitrogen atom or an oxygen atom.
  • Bicyclic ring systems include both fused ring systems, such as benzomorpholino, as well as ring systems comprising two rings joined by a single covalent bond, such as a phenylpyrazolyl or phenylpyrrolyl. If G 1 is substituted, each carbon atom of G 1 may independently have 0, 1 , or 2 substituents. In some embodiments, G 1 may have 0, 1 , 2, 3, or 4 substituents. G 1 may have any substituent.
  • some or all of the substituents of G 1 may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , CsHu, cyclic C 5 H 9 , C 6 H 13 , cyclic CeHu, etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; Ci -6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCH 3 , -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 -phenyl, etc.
  • G 1 is phenylpyrazolyl optionally substituted with 1 , 2, 3, or 4 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , OH, COR c , or R c -OH.
  • G 1 is phenylpyrrolyl optionally substituted with 1 , 2, 3, or 4 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , OH, COR c , or R c -OH.
  • G 1 is benzomorpholino optionally substituted with 1 , 2, 3, or 4 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , OH, COR c , or R c -OH.
  • G 1 may be:
  • G 1 may be:
  • R 6 may be independently a bond or C 1-3 alkyl, such as CH 2 , -CH 2 CH 2 -, -CH(CH 3 )-, -(CH 2 )3-, -CH 2 CH(CH 3 )-, etc.
  • R 6 is a bond.
  • R 6 is CH 2 .
  • R 7 may be independently a bond or C 1-3 alkyl, such as CH 2 , -CH 2 CH 2 -, -CH(CH 3 )-, -(CH 2 )3-, -CH 2 CH(CH 3 )-, etc. In some embodiments, R 7 is a bond. In some embodiments, R 7 is CH 2 .
  • Ar 2 may be optionally substituted monocyclic C 2-5 heteroaryl, such as optionally substituted pyridinyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, etc.
  • Ar 2 may have 0, 1 , or 2 substituents.
  • Ar 2 may have any substituent.
  • some or all of the substituents of Ar 2 may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
  • the substituents may be Ci-i 0 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , CsHu, cyclic C 5 H 9 , C 6 H 13 , cyclic CeHu, etc., which may be optionally substituted; CMO optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, CI, Br, I; OH; CN; N0 2 ; Ci -6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a CMO ester such as -OCOCH 3 , -C0 2 CH 3 , -OCOC 2 H 5 , -C0 2 C 2 H 5 , -OCO-phenyl, -C0 2 -phenyl, etc.
  • Ar 2 is thiazolyl optionally substituted with 1 or 2 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Ar 2 may be:
  • Cy 3 may be optionally substituted aliphatic C 2-5 heterocyclyl, such as optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted morpholino, etc. [0103] In some embodiments, Cy 3 is piperidinyl optionally substituted with 1 , 2, 3, or 4 substituents, wherein each substituent is independently F, CI, Br, R c , OR c , COR c , or R c -OH.
  • Cy 3 may be:
  • Cy 3 may be:
  • Some useful compounds may be represented by one or more of Formulas 2, 4, and 6 -41 .
  • n may be 1 , 2, 3, 4 or 5.
  • o may be 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • p may be 1 , 2, 3, 4, 5, 6, 7 or 8.
  • X 1 may be O, S, NR 2 , or CHR 2 .
  • X 2 may be O, S, NR 3 , or CHR 3 .
  • X 3 may be O, S, NR 3 , or CHR 3 .
  • q may be 1 , 2, 3, 4 or 5.
  • r may be 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • X 4 may be O, S, NR 5 , or CHR 5 .
  • R 1 -R 5 and R 8 -R 63 may be H or any substituent, such as a substituent having from 0 to 6 carbon atoms and from 0 to 5 heteroatoms, wherein each heteroatom is independently: O, N, S, F, CI, Br, or I, and/or having a molecular weight of 15 g/mol to 300 g/mol.
  • R 1 may include R A , R A -OH, R A -F, R A -CI, R A -Br, R A -I, F, CI, Br, I, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • each R 1 may independently be H; F; CI; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl- OH isomers (e.g.
  • fluoroethyl isomers fluoropropyl isomers, fluorocyclopropyl isomers, fluorobutyl isomers, fluorocyclobutyl isomers, fluoropentyl isomers, fluorocyclopentyl isomers, fluorohexyl isomers, fluorocyclohexyl isomers, chloromethyl (e.g.
  • chloroethyl isomers chloropropyl isomers, chlorocyclopropyl isomers, chlorobutyl isomers, chlorocyclobutyl isomers, chloropentyl isomers, chlorocyclopentyl isomers, chlorohexyl isomers, chlorocyclohexyl isomers, bromomethyl (e.g.
  • bromoethyl isomers bromopropyl isomers, bromocyclopropyl isomers, bromobutyl isomers, bromocyclobutyl isomers, bromopentyl isomers, bromocyclopentyl isomers, bromohexyl isomers, bromocyclohexyl isomers, iodomethyl (e.g.
  • each R 1 is independently H, F, CI, Br, I, OH, or C 1-6 alkyl optionally substituted with F, CI, Br, I, or OH. In some embodiments, R 1 may be H. With respect to Formula 2, in some embodiments, if n is 1 , then R 1 is not Br.
  • R 2 may include R A , R A -OH, R A -F, R A -CI, R A -Br, R A -I, F, CI, Br, I, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 2 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl- OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as flu
  • R 3 may include R A , R A -OH, R A -F, R A -CI, R A -Br, R A -I, F, CI, Br, I, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 3 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl- OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as flu
  • each R A may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula -C a H 2a +i or -C a H 2a -, or cycloalkyl having a formula -C a H 2a- i or -C a H 2a-2 -, wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12, such as linear or branched alkyl of a formula: -CH 3 , -CH 2 -, -C 2 H5, -C 2 H 4 -, -C 3 H7, -C 3 H 6 -, -C 4 H 9 , -C 4 H 8 -, -C5H11 , -C5H1 0 -, -CeH-13, -C 6 Hi 2 -, -C7H15, -C 7 H-
  • R A may be H or Ci -6 alkyl. In some embodiments, R A may be H or Ci -3 alkyl. In some embodiments, R A may be H, -CH 2 - or CH 3 . In some embodiments, R A may be H.
  • each R B may independently be H, or Ci_i 2 alkyl, including: linear or branched alkyl having a formula -C a H 2a+1 , or cycloalkyl having a formula -C a H 2a-1 , wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12, such as linear or branched alkyl of a formula: -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 Hn, -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 9 H 19 , -CioH 21 , etc., or cycloalkyl of a formula: -C 3 H 5 , -C 4 H 7 , -C 5 H 9 , -C 6 Hn, -C 7 H 13 , -C 8 H 15 , -C 9 H 19 , -Ci
  • R B may be H or Ci -6 alkyl. In some embodiments, R B may be H or Ci -3 alkyl. In some embodiments, R B may be H or CH 3 . In some embodiments, R B may be H. [0124] With respect to any relevant formula or structural feature herein, each R c may independently be C 1-6 alkyl, including: linear or branched alkyl having a formula -C a H 2 a + i or -C a H 2a -, or cycloalkyl having a formula -C a H 2a -i or -C a H 2a -2-, wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12, such as linear or branched alkyl of a formula: -CH 3 , -CH 2 -, -C 2 H 5 , -C 2 H 4 -, -C3H7, -C3H6-, -C 4 Hg,
  • R 4 may include R A , R A -OH, R A -F, R A -CI, R A -Br, R A -I, F, CI, Br, I, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 4 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl- OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or C 1-6 haloalkyl, such as flu
  • R 5 may include R A , R A -OH, R A -F, R A -CI, R A -Br, R A -I, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 5 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl- OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or C 1-6 haloalkyl, such as flu
  • R 8 may include H, methyl, or ethyl. In some embodiments, R 8 may be H. In some embodiments, R 8 is CH 3 .
  • R 9 may include H or methyl. In some embodiments, R 9 may be H.
  • R 10 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 10 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; methyl, ethyl, propyl isomers, cyclopropyl, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, etc.; or Ci -6 haloalkyl, such as fluoromethyl, fluoroethyl isomers, etc.
  • R 10 may be H.
  • R 10 is F.
  • R 11 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 11 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as fluor
  • R 11 may be F, CI, or CH 3 In some embodiments, R 11 may be H. In some embodiments, R 11 is F. In some embodiments, R 11 is CI. In some embodiments, R 11 is CH 3 . In some embodiments, R 11 is benzimidazol-2-yl.
  • R 12 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 12 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as fluor
  • R 12 may be F, CI, Br, CH 3 , CF 3 or -COCH 3. In some embodiments, R 12 may be H. In some embodiments, R 12 is CH 3. In some embodiments, R 12 is CI. In some embodiments, R 12 is Br. In some embodiments, R 12 is F. In some embodiments, R 12 is -COCH 3. In some embodiments, R 12 is CF 3.
  • R 10 is F and R 12 is F.
  • R 11 is F and R 12 is F.
  • R 11 is CH 3 and R 12 is CI.
  • R 11 is F and R 12 is Br.
  • R 11 is F and R 12 is Br.
  • R 11 is CI and R 12 is CI.
  • R 13 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 13 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, etc.; or methyl-OH, ethyl-OH isomers, propyl-OH isomers, or cyclopropyl-OH isomers.
  • R 13 may be H.
  • R 14 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 14 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; CH 3 ; or CH 3 OH.
  • R 15 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 15 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, etc.; or Ci -6 alkoxy, such as -O-methyl, -O-ethyl, isomers of -O- propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-cyclobut
  • R 16 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 16 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; C0 2 H; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or C 1-6 haloalkyl, such
  • R 16 may be CH 3 , C0 2 H, OH or -CH 2 CH 2 OH. In some embodiments, R 16 may be H. In some embodiments, R 16 is CH 3 . In some embodiments, R 16 is C0 2 H. In some embodiments, R 16 is -CH 2 CH 2 OH. In some embodiments, R 16 is OH.
  • R 17 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 17 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as
  • R 17 may be CH 3 , -CH 2 CH 3 , or OH. In some embodiments, R 17 may be H. In some embodiments, R 17 is CH 3 . In some embodiments, R 17 is -CH 2 CH 3 . In some embodiments, R 17 is OH .
  • R 18 may include R A , R A -OH, R A -F, F, CI, Br, I, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 18 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or Ci -6 hydroxyalkyl such as -CH 2 OH, -CH 2 CH 2 OH, etc.
  • R 18 may be H.
  • R 18 is optionally substituted phenyl, wherein any substituents may be R A , R A -OH, R A -F, F, CI, Br, I, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , or CONR A R B .
  • R 18 is unsubstituted phenyl.
  • R 18 is CH 3 .
  • R 19 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 19 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 or CH 3 .
  • R 19 may be H.
  • R 19 is CH 3 .
  • R 16 , R 17 , R 18 , and R 19 are CH 3.
  • R 20 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 20 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; C 1-3 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl; C 1-3 alkyl-OH, such as -CH 2 OH, -CH 2 CH 2 OH, etc.
  • R 20 is -CH 2 OH or -CH 2 CH 2 OH.
  • R 20 may be H.
  • R 20 is -CH 2 OH.
  • R 20 is -CH 2 CH 2 OH.
  • R 20 is -CH 2 OH or -CH 2 CH 2 OH and R 12 is I, CI, Br, or I.
  • R 21 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 21 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, etc.; is -CH 2 OH or -CH 2 CH 2 OH, etc.
  • R 21 may be H.
  • R 21 is CH 3 .
  • R 12 is CI
  • R 20 is -CH 2 OH or -CH 2 CH 2 OH
  • R 21 is CH 3
  • R 21 is CH 3 and R 20 is -CH 2 OH or -CH 2 CH 2 OH.
  • R 21 is CH 3
  • R 20 is CH 2 OH or CH 2 CH 2 OH
  • R 12 is F, CI, Br, or I.
  • R 22 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 22 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; CH 3 , etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, etc.; C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of -O-propyl, -O- cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
  • R 22 is -OCH 3 or CI.
  • R 22 may be H.
  • R 22 is -OCH 3 .
  • R 22 is -OCH 3 .
  • R 23 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 23 may be H; F; CI; CN; CF 3 ; OH ; NH 2 ; CH 3 or -CH 2 CH 3, Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC4H 9 , etc.
  • R 23 may be H.
  • R 23 is -OCH 3 .
  • R 24 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 24 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or C 1-6 haloalkyl, such as fluor
  • R 25 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 25 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; CH 3 ; CH 2 OH; or -CH 2 CH 2 OH.
  • R 25 may be H.
  • R 26 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 26 may be H.
  • R 27 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 27 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; methyl; ethyl; or propyl isomers.
  • R 27 may be H.
  • R 28 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 28 may be H.
  • R 29 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 29 may be H.
  • R 30 may include R A , R A -OH, R A -F, R A -CI, R A -Br, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 30 may be H.
  • R 31 may include H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl- OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH is
  • R 32 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 32 may be H.
  • R 33 may be H; F; CI; CN; CF 3 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; In some embodiments, R 33 may be H.
  • R 34 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 34 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as fluor
  • R 35 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 35 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, etc.
  • R 35 may be H.
  • R 36 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 36 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • R 36 may be H.
  • R 37 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc
  • R 37 may be H .
  • R 38 may include OH, F, CI, Br, CH 3 , or -CH 2 CH 3 .
  • R 38 may be H.
  • R 38 is OH.
  • R 39 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , N R A R B , COR A , C0 2 R A , OCORA, N R A COR B , CON R A R b , etc.
  • R 39 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • R 39 may be H.
  • R 40 may include R A , R A -OH, R A -F, F, CI, CN, CF 3 , COR A , C0 2 R A , OCOR A , CONR A R B , etc.
  • R 40 may be H; F; CI; CN; CF 3 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • R 40 may be H.
  • R 40 is -CH 2 CH
  • R 41 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 41 may be H.
  • R 42 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 42 may be H.
  • R 43 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 43 may be H.
  • R 44 may include R A , R A -OH, H; F; CI; CN; CF 3 ; OH; or NH 2 .
  • R 44 may be H.
  • R 45 may include H; F; CI; CN; CF 3 ; OH; NH 2 ; or methyl. In some embodiments, R 45 may be H.
  • R 46 may include R A , R A -OH, or R A -F, F; CI; CN; CF 3 ; OH; or NH 2 .
  • R 46 may be H.
  • R 47 may include R A , F; CI; CN; CF 3 ; OH; or NH 2 .
  • R 47 may be H.
  • R 48 may include H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; and C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers.
  • R 48 may be H.
  • R 49 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 49 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • R 49 may be H.
  • Ci -6 alkyl such as
  • R 49 is CI and R 21 is CH 3 .
  • R 49 is CI, R 20 is -CH 2 OH or -CH 2 CH 2 OH, and R 21 is CH 3 .
  • R 50 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 50 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; or C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • R 50 may be H.
  • R 50 may be H.
  • R 50 is CI and R 21 is CH 3 .
  • R 49 is CI, R 20 is -CH 2 OH or -CH 2 CH 2 OH, and R 21 is CH 3 .
  • R 51 may include R A , F, CI, CN, CF 3 ; OH; or NH 2 .
  • R 51 may be H.
  • R 52 may include R A , COR A , C0 2 R A , CONR A R B , etc.
  • R 52 may be H; CF 3 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.
  • R 52 may be H.
  • R 53 may include H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl- OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-
  • R 54 may include R A .
  • R 54 may be H.
  • R 55 may include R A , R A -OH, R A -F, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 55 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • R 55 may be H.
  • R 56 may include R A , COR A , C0 2 R A , CONR A R B , etc.
  • R 56 may be H; CN; CF 3 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, cyclopentyl-OH isomers
  • R 57 may include R A , R A -OH, R A -F, R A -CI, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 57 may be H; F; CI; CN; CF 3 ; OH; NH 2 ;
  • Ci -6 alkyl such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.
  • Ci -6 alkyl-OH such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.
  • Ci -6 haloalkyi such as methyl,
  • R 58 may include R A , R A -OH, R A -F, R A -CI, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
  • R 58 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, etc.
  • R 58 may be H.
  • R 59 may include R A , R A -OH, R A -F, R A -CI, R A -Br, F, CI, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 59 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or Ci -6 haloalkyl, such as methyl,
  • R 60 may include R A , R A -OH, R A -F, R A -CI, F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A , OCORA, NR A COR B , CONR A R B , etc.
  • R 60 may be H; F; CI; CN; CF 3 ; OH; NH 2 ; Ci -6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cydobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci -6 alkyl-OH, such as methyl-OH, ethyl-OH isomers, propyl-OH isomers, cyclopropyl-OH isomers, butyl-OH isomers, cyclobutyl-OH isomers, pentyl-OH isomers, cyclopentyl-OH isomers, hexyl-OH isomers, cyclohexyl-OH isomers, etc.; or C 1-6 haloalkyl, such as
  • R 61 may include R A , F; CI; CN; CF 3 ; OH; or NH 2.
  • R 61 may be H.
  • R 62 may include R A , F, CI, CN, CF 3 , N0 2 , etc. In some embodiments, R 62 may be H.
  • R 63 may include R A .
  • R 63 may be H.
  • Some embodiments may include one of the compounds below:
  • the compounds described above may be HIV inhibitors useful for prevention and/or treatment of HIV infections and/or associated diseases, disorders and conditions.
  • compositions herein disclosed comprise a therapeutically effective amount of HIV-1 small molecule inhibitors formulated for administration to a subject at risk of infection with HIV or to a patient suffering from or susceptible to an HIV infection and/or an associated disease, disorder or condition.
  • Some of the disclosed compositions include at least one pharmaceutically acceptable excipient and may optionally include at least one additional therapeutically active agent.
  • any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • pharmaceutically acceptable salts such as sodium, potassium, and ammonium salts
  • prodrugs such as ester prodrugs
  • tautomers or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • Appropriate excipients for use in the present pharmaceutical compositions may include, for example, one or more carriers, binders, fillers, vehicles, disintegrants, surfactants, dispersion or suspension aids, thickening or emulsifying agents, isotonic agents, preservatives, lubricants, and the like or combinations thereof, as suited to a particular dosage from desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. This document is incorporated herein by reference in its entirety.
  • compositions may be formulated for any desirable route of delivery including, but not limited to, parenteral, intravenous, intradermal, subcutaneous, oral, inhalative, transdermal, topical, transmucosal, rectal, interacisternal, intravaginal, intraperitoneal, bucal and intraocular.
  • parenteral, intradermal or subcutaneous formulations may be sterile injectable aqueous or oleaginous suspensions.
  • Acceptable vehicles, solutions, suspensions and solvents may include, but are not limited to, water or other sterile diluent; saline; Ringer's solution; sodium chloride; fixed oils such as mono- or diglycerides; fatty acids such as oleic acid; polyethylene glycols; glycerine; propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include one or more of the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine; propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use may include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include, but are not limited to, saline, bacteriostatic water, CREMOPHOR EL ® (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the solvent or dispersion medium may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the requited particle size in the case of dispersion and by the use of surfactants.
  • Preventing growth of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • the composition may also include isotonic agents such as, for example, sugars; polyalcohols such as manitol; sorbitol; or sodium chloride.
  • Prolonged absorption of injectable compositions can be enhanced by addition of an agent which delays absorption, such as, for example, aluminum monostearate or gelatin.
  • Oral compositions may include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterites; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, or corn starch
  • systemic administration may be by transmucosal or transdermal means.
  • penetrants may be used. Such penetrants are generally known in the art, and include, for example, detergents, bile salts, and fusidic acid derivatives.
  • Transdermal administration may include a bioactive agent and may be formulated into ointments, salves, gels, or creams as generally known in the art. Transmucosal administration may be accomplished through the use of nasal sprays or suppositories.
  • the disclosed HIV-1 small molecule inhibitors are useful in treating HIV-1 infections and/or associated diseases, disorders and conditions.
  • the pharmaceutical compositions comprising at least one small molecule inhibitor may be administered to individuals suffering from or susceptible to HIV-1 infection.
  • the pharmaceutical compositions comprising the small molecule inhibitors may be administered in a therapeutically effective amount, according to an appropriate dosing regiment.
  • an exact amount required may vary from subject to subject, depending on a subject's species, age and general condition, the severity of the infection, the particular agent(s) and the mode of administration.
  • about 0.001 mg/kg to about 50 mg/kg, of the pharmaceutical composition based on the subject's body weight is administered, one or more times a day, to obtain the desired therapeutic effect.
  • about 0.01 mg/kg to about 25 mg/kg, of the pharmaceutical composition based on the subject's body weight is administered, one or more times a day, to obtain the desired therapeutic effect.
  • a total daily dosage of the compounds and pharmaceutical compositions can be determined by the attending physician within the scope of sound medical judgment.
  • a specific therapeutically effective dose level for any particular patient or subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient or subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and other factors well known in the medical arts.
  • compositions may also be employed in combination therapies. That is, the compounds and pharmaceutically acceptable compositions presently disclosed can be administered concurrently with, prior to, or subsequent to, at least one other desired composition, therapeutic, treatment or medical procedure.
  • a particular combination of therapies administered can be determined by an attending physician and can take into account compatibility of treatments and desired therapeutic effect to be achieved. It will be appreciated that therapeutically active agents utilized in combination may be administered together in a single composition, treatment or procedure, or alternatively may be administered separately.
  • compositions comprising the disclosed small molecule inhibitors may be administered in combination with at least one other HIV inhibitors including, for example, but not limited to, one or more nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (Pis), fusion inhibitors, integrase inhibitors, chemokine receptor (CXCR4, CCR5) inhibitors and/or hydroxyurea.
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • Pro protease inhibitors
  • fusion inhibitors fusion inhibitors
  • integrase inhibitors chemokine receptor (CXCR4, CCR5) inhibitors and/or hydroxyurea.
  • CXCR4, CCR5 chemokine receptor
  • Nucleoside reverse transcriptase inhibitors include, but are not limited to, abacavir (ABC; ZIAGEN ® ), didanosine (dideoxyinosine (ddl); VIDEX ® ), lamivudine (3TC; EPIVIR ® ), stavudine (d4T; ZERIT ® , ZERIT XR ® ), zalcitabine (dideoxycytidine (ddC); HMD ® ), zidovudine (ZDV, formerly known as azidothymidine (AZT); RETROVIR ® ), abacavir, zidovudine, and lamivudine (TRIZIVIR ® ), zidovudine and lamivudine (COMBIVIR ® ), and emtricitabine (EMTRIVA ® ).
  • ABSC abacavir
  • ZIAGEN ® didanosine
  • ddl V
  • Nucleotide reverse transcriptase inhibitors include tenofovir disoproxil fumarate (VIREAD ® ).
  • Non-nucleoside reverse transcriptase inhibitors for HIV include, but are not limited to, nevirapine (VIRAMUNE ® ), delavirdine mesylate (RESCRIPTOR ® ), and efavirenz (SUSTIVA ® ).
  • Protease inhibitors (Pis) for HIV include amprenavir (AGENERASE ® ), saquinavir mesylate (FORTOVASE ® , INVIRASE ® ), ritonavir (NORVIR ® ), indinavir sulfate (CRIXIVAN ® ), nelfmavir mesylate (VIRACEPT ® ), lopinavir and ritonavir (KALETRA ® ), atazanavir (REYATAZ ® ), and fosamprenavir (LEXIVA ® ).
  • Atazanavir and fosamprenavir are new protease inhibitors that were recently approved by the U.S. Food and Drug Administration (FDA) for treating HIV-1 infection (see atazanavir (Reyataz) and emtricitabine (Emtriva) for HIV infection, Medical Letter on Drugs and Therapeutics, available online at www.medletter.com; U.S. Department of Health and Human Services (2003). Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents; available online at aidsinfo.nih.gov/guidelines.
  • FDA U.S. Food and Drug Administration
  • Fusion inhibitors may prevent fusion between the virus and the cell from occurring, and therefore, prevent HIV infection and multiplication. Fusion inhibitors include, but are not limited to, enfuvirtide (FUZEON ® ), Lalezari et al., New England J. Med., 348:2175-2185 (2003); and maraviroc (SELZENTRY ® , Pfizer).
  • An integrase inhibitor may block the action of integrase, preventing HIV-1 genetic material from integrating into the host DNA, and thereby stopping viral replication.
  • Integrase inhibitors include, but are not limited to, raltegravir (ISENTRESS ® , Merck); and elvitegravir (GS 9137, Gilead Sciences).
  • the small molecule inhibitors may be administered in combination with one or more anti-infective agents (e.g., antibiotics, etc.), pain relievers, or other agents intended to address symptoms of one or more diseases, disorders, or conditions commonly found in immunocompromised individuals but not directly caused by HIV.
  • anti-infective agents e.g., antibiotics, etc.
  • pain relievers e.g., pain relievers, or other agents intended to address symptoms of one or more diseases, disorders, or conditions commonly found in immunocompromised individuals but not directly caused by HIV.
  • the protein was prepared using the "protein preparation tool" and the structures were minimized with Macromodel software within Schrodinger Suit 201 1 .
  • a grid file encompassing the area in the cavity that contains information on the properties of the associated receptor was created. Conformational flexibility of the ligands was handled via an exhaustive conformational search. Initially, Schrodinger's proprietary GlideScore scoring function was used in standard precision (SP) mode. The 500 top-scored compounds were selected to dock again in extra precision (XP) mode to score the optimized poses. The top-scoring ligands were selected from this simulation for further study.
  • SP standard precision
  • XP extra precision
  • R substituted anilines and aromatic amines as shown in Tables 1 and 3.
  • R Primary amines as shown in Table 1. a: CICOCOOEt, NEt 3 , DCM; b: NaOH, EtOH, H 2 0; c: TBTU, NEt 3 , amine; d: HCI/dioxane (this step only required to deprotect N-Boc amines).
  • R as in Table 3. a: diethyl ether, ⁇ , ⁇ -dimethyl-formamide succinic anhydride, RT; 1 hr; b: EDC, HOBT/dimethylformamide, RNH2, RT, 4-12 hrs.
  • Oxalamide and succinimide compounds synthesized as in Example 2 were assayed for antiviral activity of oxalamide series compounds in single-cycle (TZM-bl) and multi-cycle (MT-2) inhibition assays.
  • Table 1 Structure and antiviral activity of oxalamide series compounds in single-cycle (TZM-bl) and multi-cycle (MT-2) inhibition assays.
  • the number in parenthesis indicates % toxicity at that dose.
  • the number in parenthesis indicates % toxicity at that dose.
  • TZM-bl cells were plated in 96 wells plates at 10 4 cells/well 24 hrs before infection. On the day of the infection 100 ⁇ of serial twofold dilutions of pseudovirus were added to the cells. After 3 days incubation the cells were washed 2 times with PBS and lysed with 50 ⁇ of cell culture lysis reagent (Promega). 20 ⁇ of lysates were transferred to a white 96-well plate (Costar) and mixed with 100 ⁇ of luciferase assay reagent (Luciferase Assay System, Promega).
  • the luciferase activity was immediately measured with a Tecan infinite M1000 reader (Tecan). Wells producing relative luminescence units (RLU) 4 times the background were scored as positive and the TCID 50 was calculated by the Spearman-Karber statistical method.
  • Multi-cycle neutralization assay The inhibitory activity of small molecules on infection by laboratory-adapted HIV-1 NIB strain was determined.
  • 1x10 4 MT-2 cells were infected with HIV-1 at 100 TCID 50 (50% tissue culture infective dose) (0.01 MOI) in 200 ⁇ medium in the presence or absence of small molecules at graded concentrations and incubated overnight. The culture supernatants were then removed and replaced with fresh media.
  • 100 ⁇ of culture supernatants were collected from each well, mixed with equal volume of 5% Triton X-100 and tested for p24 antigen by sandwich-ELISA. The percent inhibition of p24 production and IC 50 values were calculated by the GraphPad Prism software (GraphPad Software Inc.).
  • PBMCs were isolated from the blood of healthy donors at the New York Blood Center by standard density-gradient centrifugation using Histopaque-1077 (Sigma- Aldrich). The cells were cultured at 37 °C for 2 h. Non-adherent cells were collected and resuspended at 5 x 10 6 cells/ml in RPMI-1640 medium containing 10% (v/v) fetal bovine serum, 5 ⁇ g/ml of phytohemagglutinin, and 100 U/ml of IL-2 (Sigma-Aldrich), followed by incubation at 37 °C for three days.
  • the phytohemagglutinin-stimulated cells (5 x 10 4 cells/ml) were infected with primary HIV-1 isolates at 500 TCID 50 (0.01 MOI) in the absence or in the presence of small molecules at graded concentrations. Culture media were changed every three days and replaced with fresh medium containing freshly prepared compounds. The supernatants were collected seven days post-infection and tested for p24 antigen by ELISA. The percentage inhibition of p24 production, IC 50 and IC 90 values were calculated with GraphPad Prism software (GraphPad Software Inc.).
  • cytotoxicity of small molecules in TZM-bl cells was measured by a colorimetric method using XTT (sodium 3'-(1-(phenylamino)-carbonyl)-3,4-tetrazolium-bis(4- methoxy-6-nitro) bezenesulfonic acid hydrate), a light yellowish tetrazolium dye. Briefly, 100 ⁇ of a compound at graded concentrations was added to equal volume of cells (10 5 /ml) in wells of 96-well plates followed by incubation at 37°C for 3 days and addition of XTT (PolySciences, Inc., Warrington, PA).
  • XTT sodium 3'-(1-(phenylamino)-carbonyl)-3,4-tetrazolium-bis(4- methoxy-6-nitro) bezenesulfonic acid hydrate
  • the soluble intracellular formazan was quantitated colorimetrically at 450 nm 4 h later.
  • the percent of cytotoxicity and the CC 50 (the concentration for 50% cytotoxicity) values were calculated by the GraphPad Prism software (GraphPad Software Inc.).
  • Cytotoxicity of small molecules in MT-2 cells and PBMC was measured by the XTT ((sodium 3'-(1 -(phenylamino)-carbonyl)-3,4-tetrazolium-bis(4-methoxy-6-nitro) bezenesulfonic acid hydrate)) method. Briefly, for MT-2 cells, 100 ⁇ of a small molecule at graded concentrations was added to an equal volume of cells (10 5 cells/ml) in 96-well plates followed by incubation at 37 °C for four days, which ran parallel with the neutralization assay in MT-2 (except medium was added instead of virus).
  • PBMC peripheral blood mononuclear cells
  • cytotoxicity was measured after seven days.
  • XTT Poly- Sciences, Inc.
  • the soluble intracellular formazan was quantified colorimetrically at 450 nm 4 h later with a reference at 620 nm. The percentage cytotoxicity and the CC 50 values were calculated as described above.
  • a dye transfer assay was used to detect HIV-1 -mediated cell-cell fusion. Calcein-AM-labeled HIV-1 III B-infected H9 cells were incubated with MT-2 cells in the presence or absence of the compounds. Fused and unfused cells were counted under an inverted fluorescence microscope. The percent of inhibition was plotted against the concentrations of the inhibitors (FIG. 4A).
  • a luciferase-based assay was used to detect the fusion of HIV-1 NL4-3-Luc pseudotyped viruses expressing Env of the HIV-1 HXB2 (X4) strain with U87-T4-CXCR4 cells.
  • the compounds at graded concentrations were mixed with the virus at a final p24 concentration of 0.5 ng/ml and added to the cells and incubated. After 3 days, cells were harvested and lysed for measuring luciferase activity. Percent of inhibition was calculated and plotted against concentrations. Each assay was done in triplicate and represented as a mean ⁇ standard deviation (FIG. 4B).
  • FIG. 6A A representative dose-response plot of the neutralization assay using MT-2 cells with HIV-1 V32 is shown in FIG. 6A.
  • FIG. 6B A representative dose-response plot of the neutralization assay using PBMC with the HIV-1 92BR025 isolate (subtype C and R5-tropic) is shown in FIG. 6B.
  • NBD-556 and NBD-557 inhibited infection by both laboratory-adapted and primary strains of HIV-1 .
  • the inhibitory activities of NBD-556 and NBD-557 on infection of MT-2 cells by different laboratory-adapted HIV-1 strains, and of PBMC by different HIV-1 primary isolates, representing a diverse set of clades including both X4 and R5 viruses was determined.
  • Both compounds inhibited the laboratory-adapted HIV-1 strains NIB, MN, and V32 with IC50 values ranging from 5 to 16 ⁇ .
  • AZT-R AZT-resistant HIV-1 strain.
  • Both compounds were able to effectively inhibit that strain at 25-58 ⁇ concentrations.
  • These compounds also inhibited infection by primary isolates representing different genotypes and biotypes with varying degrees of potency (IC50: 15-103 ⁇ ) (Tables 5 and 6).
  • the assay was done in triplicate and the data are presented as mean standard deviation.
  • NBD-556 and NBD-557 block the interaction between gp120 and CD4.
  • a captured ELISA assay was first set up using recombinant gp120 from HIV-1 I IB and HIV-1 MN .
  • the compounds were incubated at graded concentrations with sCD4 (0.25 g/ml) in the wells of polystyrene plates containing recombinant gp120, which was captured by coating the plates with a sheep anti-gp120 antibody D7324.
  • Chloropeptin a potent inhibitor of gp120-CD4 interaction was used as control.
  • both NBD- 556 and NBD-557 inhibited the interaction between gp120 and CD4 at low ⁇ concentrations (Table 9) suggesting that these compounds target either gp120 or CD4.
  • SPR surface plasmon resonance
  • NBD-09027 and NBD-10007 inhibit gp120-CD4 interaction in a dose dependent manner (FIG. 7).
  • analogs were tested in a single-cycle antiviral assay and their inhibitions are less than 1 ⁇ g range which translates to -1-2 ⁇ ranges (FIG. 8A-8B).
  • Pseudo-virus capable of a single cycle infection in TZMbl cells were prepared. 293T cells were seeded in a T75 flask and transfected 24 hrs later in 15 ml medium with a mixture of 10 ⁇ g of an env-deleted backbone plasmid pSG3Aenv (AIDS Research and Reference Reagent Program cat# 1 1051 ) and 10 ⁇ g of env expression vector clade B or C reference panel DNA (AIDS Research and Reference Reagent Program cat# 1 1326 and #1 1227) using FuGENE 6 (Roche).
  • the clade B and C reference panels were designed for use as Env-pseudotyped viruses to facilitate standardized Tier 2/3 assessments of HIV-1- specific neutralizing antibodies.
  • Pseudovirus-containing supernatants were collected 2 days after transfection and stored in aliquots at -80°C.
  • Pseudo-viruses were titered by infecting the TZM-bl cells to calculate the 50% tissue culture infectious dose (TCID 50 ).
  • TZM-bl cells were plated in 96 wells plates at 10 4 cells/well 24 hrs before infection. On the day of the infection 100 ⁇ of serial twofold dilutions of pseudovirus were added to the cells.
  • NBD-09027, -1 1008, -1 1018, -1 1021 and -556 were tested on HIV-1 pseudotyped viruses expressing Env from the panel of standard reference subtype C and on two HIV-1 pseudotyped viruses expressing Env from the panel of standard reference subtype B. Briefly, 100 ⁇ of TZM-bl cells at 1x10 5 cells/ml was added to the wells of a 96-well tissue culture plate and cultured at 37°C overnight. 50 ⁇ of a test compound at graded concentrations was mixed with 50 ⁇ of the HIV-1 pseudo-virus at about 100 TCID50. After incubation at 37°C for 30 min, the mixture was added to the cells and incubated at 37°C for 3 days. The cells were then harvested and lysed and luciferase activity was determined (Table 1 1 ).

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Abstract

La présente invention concerne des composés chimiques inhibant des rétrovirus. Plus particulièrement, l'invention concerne des composés de type petites molécules inhibant des infections par, ou traitant des infections provoquées par des virus de l'immunodéficience humaine.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016044808A1 (fr) * 2014-09-19 2016-03-24 New York Blood Center, Inc. Phénylpyrrole-carboxamides substitués présentant une activité thérapeutique contre le vih
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
JP2016539982A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリミジン誘導体
WO2017035127A1 (fr) * 2015-08-24 2017-03-02 New York Blood Center, Inc. Phénylpyrrole-carboxamides substitués présentant une activité thérapeutique contre le vih
WO2017173048A1 (fr) * 2016-03-31 2017-10-05 Merck Patent Gmbh Composés inhibiteurs de cyclophilines et leurs utilisations
WO2017173049A1 (fr) * 2016-03-31 2017-10-05 Merck Patent Gmbh Composés inhibiteurs de cyclophilines et leurs utilisations
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010053583A2 (fr) 2008-11-10 2010-05-14 Dana Farber Cancer Institute Mimétiques cd4 à petite molécule et leurs utilisations
WO2013090696A1 (fr) 2011-12-14 2013-06-20 Dana-Farber Cancer Institute, Inc. Inhibiteurs de mimétiques du cd4 empêchant la pénétration du vih-1 et leurs méthodes d'utilisation
US9975848B2 (en) 2014-08-13 2018-05-22 The Trustees Of The University Of Pennsylvania Inhibitors of HIV-1 entry and methods of use thereof
WO2016190331A1 (fr) * 2015-05-25 2016-12-01 国立大学法人東京医科歯科大学 Inhibiteur d'une infection par le vih

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1099701A1 (fr) 1999-11-10 2001-05-16 Pfizer Products Inc. Amides des acides 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)amino]-quinoleine-3 carboxyliques, et méthodes pour inhiber la sécretion de l'apolipoprotéine B
EP1127883A2 (fr) 2000-02-24 2001-08-29 F. Hoffmann-La Roche Ag Oxamides comme inhibiteurs d'IMPDH
WO2005030140A2 (fr) 2003-09-26 2005-04-07 Exelixis, Inc. Modulateurs de c-met et procede d'utilisation
WO2005037779A2 (fr) 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs de dipeptidylpeptidases iv destines a influencer le fonctionnement de diverses cellules et a traiter des maladies immunologiques, inflammatoires, neuronales et autres
WO2005082895A1 (fr) 2004-02-28 2005-09-09 Boehringer Ingelheim International Gmbh Nouveaux carboxamides comme inhibiteurs du facteur xa
US20060100232A1 (en) * 2004-11-11 2006-05-11 Summers Michael F Inhibitors of HIV-1 capsid formation: substituted aryl aminomethyl thiazole ureas and analogues thereof
WO2007073505A2 (fr) 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Méthodes et compositions de traitement de la douleur
US20090170953A1 (en) * 2003-02-21 2009-07-02 Tripep Ab Indentification of compounds that inhibit replication of human immunodeficiency virus
WO2009117269A1 (fr) 2008-03-18 2009-09-24 Merck & Co., Inc. 4-hydroxypyrimidine-5-carboxamides substitués
WO2010053583A2 (fr) 2008-11-10 2010-05-14 Dana Farber Cancer Institute Mimétiques cd4 à petite molécule et leurs utilisations
CA2766056A1 (fr) 2009-06-30 2011-01-06 Merck Sharp & Dohme Corp. 4-hydroxypyrimidine-5-carboxamides substitues

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1099701A1 (fr) 1999-11-10 2001-05-16 Pfizer Products Inc. Amides des acides 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)amino]-quinoleine-3 carboxyliques, et méthodes pour inhiber la sécretion de l'apolipoprotéine B
EP1127883A2 (fr) 2000-02-24 2001-08-29 F. Hoffmann-La Roche Ag Oxamides comme inhibiteurs d'IMPDH
US20090170953A1 (en) * 2003-02-21 2009-07-02 Tripep Ab Indentification of compounds that inhibit replication of human immunodeficiency virus
WO2005030140A2 (fr) 2003-09-26 2005-04-07 Exelixis, Inc. Modulateurs de c-met et procede d'utilisation
WO2005037779A2 (fr) 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs de dipeptidylpeptidases iv destines a influencer le fonctionnement de diverses cellules et a traiter des maladies immunologiques, inflammatoires, neuronales et autres
WO2005082895A1 (fr) 2004-02-28 2005-09-09 Boehringer Ingelheim International Gmbh Nouveaux carboxamides comme inhibiteurs du facteur xa
US20060100232A1 (en) * 2004-11-11 2006-05-11 Summers Michael F Inhibitors of HIV-1 capsid formation: substituted aryl aminomethyl thiazole ureas and analogues thereof
WO2007073505A2 (fr) 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Méthodes et compositions de traitement de la douleur
WO2009117269A1 (fr) 2008-03-18 2009-09-24 Merck & Co., Inc. 4-hydroxypyrimidine-5-carboxamides substitués
WO2010053583A2 (fr) 2008-11-10 2010-05-14 Dana Farber Cancer Institute Mimétiques cd4 à petite molécule et leurs utilisations
CA2766056A1 (fr) 2009-06-30 2011-01-06 Merck Sharp & Dohme Corp. 4-hydroxypyrimidine-5-carboxamides substitues

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Medical Letter on Drugs and Therapeutics", 2003, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, article "U.S. Food and Drug Administration (FDA) for treating HIV-1 infection (see atazanavir (Reyataz) and emtricitabine (Emtriva) for HIV infection"
"Remington's Pharmaceutical Sciences", 1980, MACK PUBLISHING CO.
LALEZARI ET AL., NEW ENGLAND J. MED., vol. 348, 2003, pages 2175 - 2185
See also references of EP2753176A4

Cited By (18)

* Cited by examiner, † Cited by third party
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US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
JP2016539982A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリミジン誘導体
US10869856B2 (en) 2014-09-19 2020-12-22 New York Blood Center, Inc. Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV
US10576059B2 (en) 2014-09-19 2020-03-03 New York Blood Center, Inc. Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV
US10413527B2 (en) 2014-09-19 2019-09-17 New York Blood Center, Inc. Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV
US10137107B2 (en) 2014-09-19 2018-11-27 New York Blood Center, Inc. Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV
WO2016044808A1 (fr) * 2014-09-19 2016-03-24 New York Blood Center, Inc. Phénylpyrrole-carboxamides substitués présentant une activité thérapeutique contre le vih
US11059808B2 (en) 2014-09-19 2021-07-13 New York Blood Center, Inc. Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV
US11571409B2 (en) 2014-09-19 2023-02-07 New York Blood Center, Inc. Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV
WO2017035127A1 (fr) * 2015-08-24 2017-03-02 New York Blood Center, Inc. Phénylpyrrole-carboxamides substitués présentant une activité thérapeutique contre le vih
WO2017173049A1 (fr) * 2016-03-31 2017-10-05 Merck Patent Gmbh Composés inhibiteurs de cyclophilines et leurs utilisations
WO2017173048A1 (fr) * 2016-03-31 2017-10-05 Merck Patent Gmbh Composés inhibiteurs de cyclophilines et leurs utilisations

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